1. Field of the Invention
The present invention relates to Wondonin A and a process for preparing the same, more specifically, to Wondonin A which is extracted from a two-sponge association of phylum Porifera (sponge) and has antiangiogenic activity, and a process for preparing the same.
2. Background of the Invention
In general, malignant tumors contain a lot of hypoxic cells due to an inadequate vasculature (see: Moulder and Rockwell, Cancer Metastasis Rev., 5:313-341, 1987; Vaupel et al., Cancer Res., 49:6449-6465, 1989) or a change in a supply of red blood cells in intratumoral microvessels (see: Kimura et al., Cancer Res., 56:5522-5528, 1996). Although these hypoxic tumor cells may be reoxygenized by reopening of temporally closed or clogged microvessels not to inhibit tumor cell growth (see: Brown, J. M., Br. J. Radiol., 52:650-656, 1979) or reoxygenized by inactivation of tumor cells by fractionated radiation therapy (see: Kallman, R. F., Radiology, 105:135-142, 1972) by which some of them may be converted into normoxic cells, it has been known that hypoxic cells are generally more resistant to radiation therapy or conventional chemotherapy (see: Teicher et. al., Cancer Res., 41:73-81, 1981; Gatenby et al., Int. J. Radiat. Oncol. Biol. Phys., 14:831-838, 1988; Teicher et. al., Cancer Metastasis Rev., 13:139-168, 1994).
Although the adaptation mechanism of tumor cells to a low oxygen tension has not been understood clearly, hypoxia has been known to affect the pattern of gene expression in tumor cells (see: Brown and Giaccia, Int. J. Radiat. Biol., 65:95-102, 1994) and it has been reported that stress reaction of normoxic cells is induced by low-oxygen environment and, in consequence, synthesis of stress proteins is induced in vivo and in vitro (see: Guttman et al., Cell, 22:229-307, 1980; Heacock and Sutherland, Br. J. Cancer, 62:217-225, 1990; Iwaki et al., Circulation, 87:2023-2032, 1993). For example, Baek et al. demonstrated that the synthesis of heat shock proteins such as hsp70 and hsp25 is upregulated in mouse radiation-induced fibrosarcoma (RIF) cells by hypoxia, and hypoxic tumor cells with increased level of heat shock proteins are more resistant to hypoxia than normoxic cells (see: Baek et al., J. Biochem. and Mol. Biol., 32:112-118, 1999).
It has been demonstrated that growth factors such as VEGF (vascular endothelial cell growth factor) (see: Stein et al., Mol. Cell. Biol., 15:5363-5368, 1995), EPO (erythropoietin) (see: Wang and Semenza, Blood, 82:3610-3615, 1993) and TGF xcex2-1 (transforming growth factor xcex2-1) (see: Brown et al., EXS., 79:233-269, 1997) required for angiogenesis which is an essential process for progression and metastasis of hypoxic tumor cells described above can be upregulated by hypoxia. Hence, cooperative induction of stress protein and angiogenesis factor genes are understood to render tumor cells adaptable to low oxygen stress, helping progression of tumor cells toward more malignant phenotype.
In order to overcome problems caused by hypoxic tumor cells, three methods are conventionally employed in the art: (i) oxygenation of tumor cells; (ii) attenuation of hypoxic cells with radiation or chemotherapy; and (iii) hypoxic cell death by a hypoxic cell cytotoxin (see: Brown and Kong, J. Intl. Cancer Inst., 83:178-185, 1991). However, hypoxic tumor cells are resistant to both radiation and chemotherapy, thus, researchers on development of methods which can increase curative efficiency for tumor cells are being undertaken, and yet, side effects of the substances which inhibit synthesis of proteins required for angiogenesis are so severe that there has been no progress of the research.
Under the circumstances, there are strong reasons for exploring and developing natural compounds which has antiangiogenic activity without side effects.
The present inventors have made an effort to develop a natural product which has antiangiogenic activity without side effects, and discovered that Wondonin A, a novel compound extracted from phylum Porifera, can exert inhibitory activity against angiogenesis without cytotoxicity.
A primary object of the present invention is, therefore, to provide Wondonin A extracted from phylum Porifera.
The other object of the invention is to provide a process for preparing Wondonin A.